CN115337273A - Preparation method of aminocyclohexanoic acid preparation - Google Patents

Preparation method of aminocyclohexanoic acid preparation Download PDF

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Publication number
CN115337273A
CN115337273A CN202210954080.9A CN202210954080A CN115337273A CN 115337273 A CN115337273 A CN 115337273A CN 202210954080 A CN202210954080 A CN 202210954080A CN 115337273 A CN115337273 A CN 115337273A
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preparation
vigabatrin
acid
purified water
stabilizer
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王众勤
李守峰
柏威龙
李博莉
梁华国
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Shanghai Aucta Pharmaceuticals Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Nutrition Science (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Physiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses a preparation method of a preparation of aminocyclohexanoic acid, which comprises the following steps: (1) Weighing the raw material medicines of vigabatrin, an excipient, a pH stabilizer, an antioxidant and purified water according to the dosage; (2) Putting part of the purified water in a prescription amount into a container, and adding vigabatrin, an excipient, a pH stabilizer and purified water; (3) stirring until the mixture is completely dissolved, and adding the balance of water; (4) Filtering the liquid medicine prepared in the step (3), filling the liquid medicine into an injection bottle, and performing freeze drying; and (4) secondary drying, capping and packaging to obtain a finished product. The freeze-dried preparation prepared by the invention has a loose porous structure, can ensure that the medicine is easy to redissolve and recover the activity, and has low water content and easy long-term stable storage; the injection can be produced by using a sterile process and used for injection, and powder can also be prepared to be directly taken orally or be dissolved into solution by adding water for oral administration, so that multiple using modes of the preparation are realized, and the clinical use is facilitated.

Description

Preparation method of aminocyclohexanoic acid preparation
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a preparation method of an aminocaproic acid preparation.
Background
Vigabatrin (Vigabatinn), a chemical with the chemical name of 4-amino-5-hexenoic acid and the molecular formula of C 6 H 11 NO 2 Molecular weight is 129.157. Vigabatrin is an analog of gamma-aminobutyric acid (GABA) and binds specifically to GABA aminotransferase and is irreversible, resulting in increased GABA concentration in the brain, thereby exerting an antiepileptic effect. Vigabatrin is a second batch of children drug which encourages research and development and application and is jointly released by the Ministry of health, industry and informatization and food and drug supervision and management administration and is used for treating infantile spasm. Infantile Spasm (IS), also known as West syndrome, IS an age-dependent epilepsy syndrome specific to infants, the incidence of the disease IS 0.016% -0.042%, more than 90% of infants suffer from the disease within 1 year of age, the onset peak age IS 4~6 months, and the symptoms are mainly manifested as struggle of intractable spasm sustained attack, mental motor development retardation and electroencephalogram graphic failure. Children suffering from the diseases are often accompanied by intellectual disabilities and various types of defects of special cognitive abilities, the prognosis is poor, and the fatality rate is higher by 5-30%. Vigabatrin is recommended by the chinese antiepileptic association in the 2015 edition of "clinical guidelines" as a first line treatment for infantile spasms caused by tuberous sclerosis. The traditional Chinese medicine composition can be clinically used for adjuvant therapy of adults or children epileptics aged 10 years and older than 10 years, and can be used for treating intractable complex partial seizure epileptics which are ineffective by other medicines and have potential benefits higher than the risk of vision damage.
Vigabatrin currently exists in the market in only two dosage forms, oral tablets and powders. Vigabatrin has an amino acid structure with the following formula:
Figure DEST_PATH_IMAGE002
an impurity related substance A having the following structure is easily generated under acidic conditions, as shown in the following figure
Figure DEST_PATH_IMAGE004
；
It is easily oxidized and deteriorated in an alkaline environment, and thus, a strict preparation process is required to prevent an increase in the content of impurities in both oral tablets and oral powders. In most reusable oral solutions, preservatives are added to inhibit microbial growth and contamination and biodegradation, and to ensure that the pharmaceutical product is safe and effective. After the preservative is dissolved in the solution, the drug solution in the container can meet the requirement of microbial limit in the process of multiple use. However, limited oral preservatives generally work at low pH where vigabatrin is unstable. Some preservatives are insoluble or dissolve very slowly in low pH environments unless heat or ultrasound is used to facilitate dissolution, which is inconvenient for the patient or medical personnel. The vigabatrin is unstable under the acidic pH, and the poor solubility of the preservative is a practical problem for an effective vigabatrin solution system used for multiple times. Further, although an oral tablet is a suitable formulation, it is often inconvenient for children patients with poor compliance or elderly patients with dysphagia to use, and thus there is a need to develop more dosage forms to meet the needs of different types of patients.
Disclosure of Invention
The invention mainly aims to provide a preparation method of an aminocaproic acid preparation, which can effectively solve the problems mentioned in the background technology.
In order to achieve the purpose, the invention adopts the technical scheme that:
a method of preparing an aminocaproic acid formulation comprising the steps of: (1) Weighing the raw material medicines of vigabatrin, an excipient, a pH stabilizer, an antioxidant and purified water according to the dosage; (2) Putting part of the formula amount of purified water into a container, and adding vigabatrin, an excipient, a pH stabilizer and purified water; (3) stirring until the mixture is completely dissolved, and adding the balance of water; (4) Filtering the liquid medicine prepared in the step (3), filling the liquid medicine into an injection bottle, and performing freeze drying; and (5) drying for the second time, capping and packaging to obtain a finished product.
Further, the excipient is selected from one or more of sucrose, glucose, sorbitol, sucralose, aspartame, saccharin sodium or mannitol, and is preferably mannitol; the excipient accounts for 50-150% of the vigabatrin by mass, preferably 80-120% of the vigabatrin by mass, and most preferably 100% of the vigabatrin by mass.
Further, the pH stabilizer of the present invention is selected from one or any combination of citrate, citric acid, fumarate, fumaric acid, tartrate, tartaric acid, phosphoric acid, dihydrogen phosphate and dihydrogen phosphate, preferably dihydrogen phosphate; the mass of the pH stabilizer is 4-10% of vigabatrin, preferably 5-9%, or preferably 6-8%.
Further, the antioxidant of the invention is selected from one or more of lycopene, procyanidine, thiosulfate, sulfite, bisulfite and ascorbic acid; the content of the antioxidant is 0.04-0.2% of the vigabatrin by mass, preferably 0.06-0.16% of the vigabatrin by mass, or preferably 0.08-0.12% of the vigabatrin by mass, and most preferably 0.10% of the vigabatrin by mass.
Further, the amount of purified water in step (2) of the method of the present invention is 60 to 90% of the total water used.
Further, the step (4) of filtration of the method of the present invention is performed by using a filter with a pore size of 0.15-0.35 micron, preferably a filter with a pore size of 0.20-0.30 micron, and most preferably a filter with a pore size of 0.24 micron.
Further, the injection bottle in the step (4) of the invention is a penicillin bottle; the freeze drying comprises the following steps: precooling the filled liquid medicine to-80 to-40 ℃ within 30-120 minutes, keeping for 2-6 hours, then vacuumizing, adjusting the temperature to-20 to-10 ℃ within 20-60 minutes, and sublimating for 10-60 hours again; preferably pre-cooled to-70 to-50 ℃ or-65 to-55 ℃.
Further, the secondary drying of step (5) of the present invention comprises vacuum drying at 0 ℃ for 2 to 6 hours, and then vacuum drying at 20 to 30 ℃ for 2 to 6 hours.
Further, the process of the present invention produces a product having a moisture content of no greater than 3%, preferably no greater than 2%, more preferably no greater than 1%, and most preferably no greater than 0.8%.
Further, the mass ratio of vigabatrin to purified water in the preparation method of the vigabatrin freeze-dried preparation is 0.01-0.2:1, preferably 0.02 to 0.18:1 or 0.05-0.15:1 or 0.08-0.12:1 or 0.10:1.
further, the invention provides a vigabatrin freeze-dried preparation prepared by the method.
Furthermore, the invention also provides application of the vigabatrin freeze-dried preparation prepared by the method in preparation of anti-epileptic drugs.
In addition, the invention provides a using method of the freeze-dried vigabatrin preparation, and the using method comprises the steps of dissolving the freeze-dried preparation in water for injection, including intravenous drip, intramuscular injection and the like; the application method can also be used for directly taking the freeze-dried preparation orally, taking the freeze-dried preparation with water or dissolving the freeze-dried preparation into a solution for oral administration.
Compared with the prior art, the invention has the following beneficial effects:
1. the freeze-dried preparation prepared by the method has a loose porous structure, can ensure that the medicine is easy to redissolve and recover the activity, and has low water content and easy long-term stable storage.
2. Can be used for injection, and has rapid onset of drug action. Meanwhile, the eutectic porous structure of the freeze-dried product can be quickly dissolved to release the medicine, so that the product prepared by the technology can be directly orally taken, and can also be prepared into a solution by adding water to be orally taken, and the freeze-dried product is particularly suitable for children patients with poor medicine taking compliance or old patients with dysphagia. Really realizes multiple use modes of the preparation and is convenient for clinical use.
3. The product prepared by the method is prepared at low temperature, and the generation of cyclization impurities and other impurities is effectively avoided.
4. The product prepared by the invention is prepared at low temperature, and can effectively avoid bacterial breeding without adding extra preservative after degerming treatment; the aseptic filling is carried out after the preparation, and the problem of bacteria can not be generated in the placing process.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.
Example 1
Accurately weighed 50000 mg vigabatrin, 50000 mg mannitol, 3000 mg sodium dihydrogen phosphate, sodium thiosulfate 50 mg, and 1000 ml purified water. Vigabatrin, mannitol, sodium dihydrogen phosphate and sodium thiosulfate are dissolved in 800 ml purified water, stirred uniformly and the rest of the purified water is added. Filtering the obtained liquid medicine with a filter membrane with the aperture of 0.24 micron, and filling the filtered liquid medicine into 100 penicillin bottles, wherein each penicillin bottle approximately contains 500 mg vigabatrin. And (3) pre-cooling the liquid medicine to-60 ℃ for 2.5 hours, then carrying out vacuum pumping operation, adjusting the temperature to-15 ℃ within 30 minutes, and continuing for 30 hours until loose white solids are formed and no collapse is caused. Heating to 0 deg.C, vacuumizing for 3 hr, vacuum drying at 25 deg.C for 3 hr, and packaging.
Example 2
50000 mg vigabatrin, 50000 mg glucose, 3000 mg sodium dihydrogen phosphate, sodium bisulfite 40 mg and 1000 ml purified water were accurately weighed. Vigabatrin, glucose, sodium dihydrogen phosphate and sodium bisulfite were dissolved in 850 ml purified water, stirred well and the balance of purified water was added. Filtering the obtained liquid medicine with a filter membrane with the aperture of 0.24 micron, and filling the filtered liquid medicine into 100 penicillin bottles, wherein each penicillin bottle approximately contains 500 mg vigabatrin. And (3) pre-cooling the liquid medicine to-50 ℃ for 2.5 hours, then carrying out vacuum pumping operation, adjusting the temperature to-20 ℃ within 40 minutes, and continuing for 30 hours until loose white solids are formed and no collapse is caused. Heating to 0 ℃, continuing vacuumizing for 3 hours, then transferring the obtained solid to a vacuum drying oven, carrying out vacuum drying for 2 hours at the temperature of 25 ℃, pressing and packaging to obtain a finished product.
Example 3
50000 mg vigabatrin, 50000 mg fructose, 3000 mg sodium dihydrogen phosphate, ascorbic acid 60 mg and 1000 ml purified water were accurately weighed. Vigabatrin, fructose, sodium dihydrogen phosphate and ascorbic acid were dissolved in 750 ml purified water, stirred well and the balance of purified water was added. Filtering the obtained liquid medicine with a filter membrane with the aperture of 0.24 micron, and filling the filtered liquid medicine into 100 penicillin bottles, wherein each penicillin bottle approximately contains 500 mg vigabatrin. And (3) semi-stoppering the filled penicillin bottle, precooling the liquid medicine to-40 ℃ for 4 hours, vacuumizing, adjusting the temperature to-10 ℃ within 30 minutes, and keeping for 30 hours until loose white solid is formed without collapse. Heating to 0 deg.C, vacuumizing for 4 hr, transferring the obtained solid to vacuum drying oven, vacuum drying at 25 deg.C for 3 hr, and packaging to obtain the final product.
Test example 1: moisture content test
Samples were taken and the moisture content of the white solids obtained in examples 1-3 was measured using an MKS-520 Karl Fischer moisture meter to be 0.58%, 0.66% and 0.73%, respectively, and the samples obtained in examples 1-3 had low and uniform moisture content.
Test example 2: detection of related substances (impurity A) (HPLC method)
Figure DEST_PATH_IMAGE006
Wherein the main degradation impurity A has a structure of
Figure DEST_PATH_IMAGE008
Column A is a newly prepared freeze-dried preparation, column B is test data of 6 months of placing the freeze-dried preparation under the conditions of 25 ℃ plus or minus 2 ℃ and 60% plus or minus 5% of relative humidity under the sealing condition and sampling and detecting at the 6 th month; column C is test data of 6 months of the freeze-dried preparation placed under the conditions of 40 ℃ plus or minus 2 ℃ and 75% plus or minus 5% of relative humidity and sampling detection at month 6. The data show that the related substance A of the freeze-dried preparation prepared by the invention is hardly detected and can keep long-term stability.
Test example 3: and (3) detecting microorganisms:
the lyophilized formulations prepared in examples 1 to 3 were allowed to stand at 40 ℃. + -. 2 ℃ and a relative humidity of 75%. + -. 5% for 6 months, and a sample was taken at the 6 th month for microbial detection.
Figure DEST_PATH_IMAGE010
The above data indicate that the lyophilized formulation prepared in accordance with the present invention can be stored for extended periods of time in harsh environmental conditions while still meeting the desired microbial limits without the addition of preservatives.
Test example 4: and (3) testing the redissolution time:
the freeze-dried preparations prepared in examples 1 to 3 were subjected to a reconstitution test, and 10ml of distilled water was added to each of the freeze-dried preparations prepared in examples 1 to 3 with a syringe needle, shaken by hand, observed for properties, and timed with a stopwatch until the solution became clear and transparent.
Meanwhile, the commercially available vigabatrin granules (specification 500 mg) were used as a control, and the relative reconstitution time was examined in the same manner, and the results are shown in the following table:
test sample Example 1 Example 2 Example 3 Commercially available product
Reconstitution time(s) 13 12 13 119
The data show that the product prepared by the method has good redissolution time repeatability and shorter redissolution time, can be conveniently prepared into solution for use, and can be used for intravenous drip and intramuscular injection according to actual conditions. If necessary, the penicillin bottle stopper can be opened to prepare oral solution for direct administration.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (10)

1. A method for preparing a preparation of aminocyclohexanoic acid, comprising the steps of: (1) Weighing the raw material medicines of vigabatrin, an excipient, a pH stabilizer, an antioxidant and purified water according to the dose; (2) Putting part of the formula amount of purified water into a container, and adding vigabatrin, an excipient, a pH stabilizer and purified water; (3) stirring until the mixture is completely dissolved, and then adding the rest of water; (4) Filtering the liquid medicine prepared in the step (3), filling the liquid medicine into an injection bottle, and performing freeze drying; (5) secondary drying, capping and packaging to obtain a finished product;
the excipient is selected from one or more of sucrose, glucose, fructose, sorbitol, sucralose, aspartame, saccharin sodium or mannitol; the excipient accounts for 50-150% of the vigabatrin by mass;
the freeze drying comprises the following steps: pre-cooling the filled liquid medicine to-80 to-40 ℃ within 30-120 minutes, keeping for 2-6 hours, then vacuumizing, adjusting the temperature to-20 to-10 ℃ within 20-60 minutes, and sublimating for 10-60 hours again.
2. The method for preparing a preparation of aminocyclohexanoic acid as claimed in claim 1, wherein said pH stabilizer is selected from one or any combination of citrate, citric acid, fumarate, fumaric acid, tartrate, tartaric acid, phosphoric acid, dihydrogen phosphate, and dihydrogen phosphate; the mass of the pH stabilizer is 4-10% of the vigabatrin.
3. The method for preparing a preparation of aminocaproic acid according to claim 1, wherein the antioxidant is selected from one or more of lycopene, procyanidin, thiosulfate, sulfite, bisulfite, ascorbic acid; the content of the antioxidant is 0.04-0.2% of the weight of the vigabatrin.
4. The method of claim 1, wherein the amount of purified water in step (2) is 60-90% of the total prescribed amount of water.
5. The method for preparing an aminocaproic acid preparation as claimed in claim 1, wherein said filtering of step (4) is performed using a filter having a pore size of 0.10 to 0.35 μm.
6. The method for preparing a preparation of aminocyclohexanoic acid as claimed in claim 1, wherein the injection bottle of step (4) is a vial of cillin.
7. The method of claim 1, wherein the secondary drying of step (5) comprises vacuum drying at 0 ℃ for 2 to 6 hours followed by vacuum drying at 20 to 30 ℃ for 2 to 6 hours.
8. The method of claim 1, wherein the method produces a product having a water content of no greater than 3%.
9. The method for preparing a vigabatrin preparation according to claim 1, wherein the mass ratio of vigabatrin to purified water is 0.01-0.2:1.
10. use of vigabatrin preparation prepared by the method of any one of claims 1-9 in the preparation of an antiepileptic drug.
CN202210954080.9A 2022-08-10 2022-08-10 Preparation method of aminocyclohexanoic acid preparation Pending CN115337273A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114642633A (en) * 2022-04-15 2022-06-21 上海奥科达生物医药科技有限公司 Vigabatrin preparation liquid composition

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114642633A (en) * 2022-04-15 2022-06-21 上海奥科达生物医药科技有限公司 Vigabatrin preparation liquid composition

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